The fetal mortality rate in pregnancies with severe intrauterine growth restriction (IUGR) and preeclampsia (PE) approaches 50%. In this ARRA application, we propose experiments to elucidate the mechanisms through which inflammation promotes irreversible placental damage in these pregnancies which result in a life-threatening reduction in the the flow of nutrients from mother to fetus. Our preliminary results show that hypoxia-reperfusion injury likely triggers an interleukin-1 (IL-1 )-!3-driven inflammatory cascade in placental villus core fibroblasts (FIBs) in pregnancies with IUGR and PE. Importantly, we observed that treatment with glucocorticoid (GC), and the pineal gland peptide melatonin (MT), suppressed IL-!3 effects on cytokine expression in FIBs. It is our working hypothesis that ROS promote placental damage in IUGR and PE through an inflammatory cytokine response in the core of the placenta that accompanies and/or precedes damage to the syncytium. A corollary to this hypothesis is that these deleterious pathways can be suppressed by treatment with GC and MT. Our Specific Aims are: 1) to test the hypothesis that GC and MT treatment effectively suppresses an IL-!3-driven inflammatory cytokine cascade in core FIBs;2) to establish molecular signatures of the ROS-driven inflammatory response using placental perfusion methodology;and 3) To identify novel pathways of placental pathophysiology in pregnancies with IUGR and/or PE. For studies, we will couple physiologically relevant in vitro techniques of primary cell culture and dual (maternal + fetal) placental perfusion with state of the art molecular methodologies including laser capture microdissection (LCMD) and real-time quantitative PCR (qRTPCR). Severe IUGR is a major cause of fetal mortality, and placental dysfunction is known to playa key role in this devastating pregnancy outcome. Proposed studies will provide insight into the pathogenesis of placental damage in IUGR and PE, test potential therapeutic interventions, and elucidate novel markers in these pregnancies. We thank the NIH for considering two additional years of funding for our now long-standing studies examining placental pathophysiology in preeclampsia (PE) and intrauterine growth restriction (IUGR). We have decided to modify our Specific Aims to comply with the shortened period of potential funding. However, we feel that despite modifications to the original research plan, our application provides an exciting and novel framework for elucidating pathways of placental damage in IUGR and PE.